New treatment strategies for HIV-associated lymphomas
| Drug . | Study . | Mechanisms of action . | Disease . | Major results . |
|---|---|---|---|---|
| Oncolytic strategy | ||||
| Bortezomid (proteasome and HDAC inhibitor) plus ICE/R | Phase 1 | Potent oncolytic activity, cytotoxicity, inductor of apoptosis, synergistic/additive activity with CT, AZT | Relapsed/refractory DLBCL, PBL, PEL, HL | CR 77% 1-y OS 57% |
| Rapamycin (mTOR inihibitor) | Preclinical | Oncolytic activity, cytostatic activity | GHV-related malignancies | Increase expression of Zta and Rta, inihibition of mTOR Complex 1 |
| PEP005 (ingenol-3-angelate) plus JQ1 (BET inhibitor) | Preclinical | “Shock and Kill” strategy PEP005:oncolytic activity, inductor of apoptosis, inductor of NF-xB signaling JQ1: histone modification, inhibition of NF-κB signaling | PEL | Inhibition of PEL growth in vitro, delay of PEL growth in PEL xenograft tumor model. |
| Targeted therapy strategy | ||||
| Brentuximab vedotin (anti-CD30 monoclonal antibody plus microtubule-disrupting agent, MMAE) plus AVD | Phase 1/2 | Cytotoxicity, arrest cell cycle inductor apoptosis | HL | CR 100% 2-y PFS 100% with manageable toxicity |
| MLN0128 (mTOR inhibitor) | Preclinical | Cytotoxicity, inductor of apoptosis | Chemoresistant or rapamycin-resistant PEL | Inhibition of mTOR complex 1 and 2 in vitro and mouse model |
| Immunomodulatory strategy | ||||
| Pembrulizumab (monoclonal antibody-anti-PD-1) | Phase 1 | Inhibition of PD-1/PD-L1 axis | HL, PEL, DLBCL | Clinical benefit, with acceptable toxicity. Alert for polyclonal KSHV-associated B-cell proliferation |
| Lenalidomide, pomalidomide (thalidomide analogs) | Preclinical | Inhibition of MHC-I downregulation, inductors of ICAM-1 and B7-2 expression, inhibition of NF-κB signaling, antiangiogenesis | KSHV-related malignancies | Prevention of immune evasion, anti-proliferative effects |
| Daratumumab (anti-CD38 monoclonal antibody) | Preclinical case report | Cytotoxicity, elimination of CD38-positive regulatory cells (Tregs, Bregs, NK cells, and MDSCs) | KSHV-related malignancies | Antiproliferative effects, Immune-modulatory activities |
| Drug . | Study . | Mechanisms of action . | Disease . | Major results . |
|---|---|---|---|---|
| Oncolytic strategy | ||||
| Bortezomid (proteasome and HDAC inhibitor) plus ICE/R | Phase 1 | Potent oncolytic activity, cytotoxicity, inductor of apoptosis, synergistic/additive activity with CT, AZT | Relapsed/refractory DLBCL, PBL, PEL, HL | CR 77% 1-y OS 57% |
| Rapamycin (mTOR inihibitor) | Preclinical | Oncolytic activity, cytostatic activity | GHV-related malignancies | Increase expression of Zta and Rta, inihibition of mTOR Complex 1 |
| PEP005 (ingenol-3-angelate) plus JQ1 (BET inhibitor) | Preclinical | “Shock and Kill” strategy PEP005:oncolytic activity, inductor of apoptosis, inductor of NF-xB signaling JQ1: histone modification, inhibition of NF-κB signaling | PEL | Inhibition of PEL growth in vitro, delay of PEL growth in PEL xenograft tumor model. |
| Targeted therapy strategy | ||||
| Brentuximab vedotin (anti-CD30 monoclonal antibody plus microtubule-disrupting agent, MMAE) plus AVD | Phase 1/2 | Cytotoxicity, arrest cell cycle inductor apoptosis | HL | CR 100% 2-y PFS 100% with manageable toxicity |
| MLN0128 (mTOR inhibitor) | Preclinical | Cytotoxicity, inductor of apoptosis | Chemoresistant or rapamycin-resistant PEL | Inhibition of mTOR complex 1 and 2 in vitro and mouse model |
| Immunomodulatory strategy | ||||
| Pembrulizumab (monoclonal antibody-anti-PD-1) | Phase 1 | Inhibition of PD-1/PD-L1 axis | HL, PEL, DLBCL | Clinical benefit, with acceptable toxicity. Alert for polyclonal KSHV-associated B-cell proliferation |
| Lenalidomide, pomalidomide (thalidomide analogs) | Preclinical | Inhibition of MHC-I downregulation, inductors of ICAM-1 and B7-2 expression, inhibition of NF-κB signaling, antiangiogenesis | KSHV-related malignancies | Prevention of immune evasion, anti-proliferative effects |
| Daratumumab (anti-CD38 monoclonal antibody) | Preclinical case report | Cytotoxicity, elimination of CD38-positive regulatory cells (Tregs, Bregs, NK cells, and MDSCs) | KSHV-related malignancies | Antiproliferative effects, Immune-modulatory activities |
AVD, doxorubicin, vinblastine, dacarbazine; BET, bromodomain extra terminal protein; Bregs, regulatory B cells; CT, chemotherapy; GHV, gammaherpesvirus; HDAC, histone deacetylases; ICAM-1, intercellular cell adhesion molecule-1;ICE/R, ifosfamide, carboplatin, etoposide/rituximab; MDSCs, myeloid-derived suppressor cells; MHC-1, major histocompatibility complex-1; MMAE, monomethyl auristatin; mTOR, mammalian target rapamycin; NF-κB, nuclear factor κB; NK, natural killer; PD-L1, programmed death ligand 1; Tregs, regulatory T cells; zta and rta, 2 immediate-early transcription factors that regulate the expression of key EBV lytic genes.